This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Maternal cigarette smoking has been associated with a variety of adverse fetal, infant, and childhood developmental outcomes. In the United States alone, approximately one million infants are exposed prenatally to cigarette smoke each year! Although maternal cigarette smoking during pregnancy is a well documented risk factor for low birth weight, with its attendant complications for infant/childhood development, a direct linkage between prenatal cigarette smoke exposure and postnatal neurobehavioral/cognitive impairment remains poorly defined. The global objective of the present research program is to establish mouse-human experimental correlates to mechanistically investigate the neuroanatomical, cellular and molecular substrates underlying maternal cigarette smoking-induced defects in neuro/cognitive development. Since the hippocampus subserves a central role [unreadable]across species [unreadable] in neuro/cognition, especially in the information processing involved in learning and memory, the central hypothesis under investigation is that maternal tobacco use during pregnancy interferes with the cellular and molecular ontogenesis of the hippocampus, resulting in altered hippocampus-dependent learning and memory in the offspring. The animal studies conducted under this research program employ a mouse model, established in our laboratory, in which developmental (gestational and early postnatal) inhalation exposure to cigarette smoke simulates human maternal smoking during pregnancy. Preliminary examination of functional (behavioral) deficits in hippocampus-dependent learning/memory in animals developmentally exposed (gestational day 1-18 and postnatal days 1-21) to cigarette smoke or ambient air demonstrated that such cigarette smoke exposure affects neurodevelopment and results in spatial learning and cognitive deficits. Moreover, developmental cigarette smoke exposure results in increased anxiety- and depression-like behavior the these animals. Although no alterations in the gross or cellular morphology of the hippocampus from developmentally cigarette smoke-exposed offspring are apparent from our preliminary analyses, gene expression profiling of the isolated hippocampus from the exposed animals indicates significant alterations in the expression of various genes involved in neuronal signaling, learning and memory, among others. Both the assessments of hippocampal dependent behavioral functions proposed in Specific Aim #1 and the assessments of hippocampal gross and cellular morphology proposed in Specific Aim #2 are targeted for completion in the coming 6 months. Successful completion of the these studies, along with those proposed in Specific Aims #3 and #4 of the Research Program will aid in understanding the effects of, and mechanisms underlying, in utero tobacco smoke exposure on neuro/cognitive development in infants and children, and [unreadable]long-term [unreadable] will facilitate the diagnosis of, and intervention into, learning disabilities and other cognitive impairments in children affected by prenatal maternal tobacco abuse.